USPTO Patents Application 09993647

WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau

PCT

INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(51) International Patent Classification 5 :

C07D 409/12, A61K 31733, C07D 213/75,
417/12, 401/12, 403/12, 413/12

Al

(11) International Publication Number:
(43) International Publication Date:

WO 94/14801

7 July 1994 (07.07.94)

(21) International Application Number: PCT/EP93/03666

(22) International Filing Date: 21 December 1993 (21.12.93)

(30) Priority Data:
9227048.7
9304414.7
9306459.0

29 December 1992 (29.12.92) GB
4 March 1993 (04.03.93) GB
29 March 1993 (29.03.93) GB

(71) Applicant (for all designated States except US): SMTTHKLINE

BEECHAM PLC [GB/GB]; New Horizons Court, Brentford,
Middlesex 9EP TW8 (GB).

(72) Inventors; and

(75) Inventors/Applicants (for US only): FORBES, Ian, Thomson
[GB/GB]; SmithKline Beecham Pharmaceuticals, Coldnar-
bour Road, The Pinnacles, Harlow, Essex CM19 5 AD (GB).
MARTIN, Roger, Thomas [GB/GB]; SmithKline Beecham
Pharmaceuticals, Coldharbour Road, The Pinnacles, Harlow,
Essex CM19 5 AD (GB). JONES, Graham, Elgin [GB/GB];
SmithKline Beecham Pharmaceuticals, Coldharbour Road,
The Pinnacles, Harlow, Essex CM19 5 AD (GB).

(74) Agent: GJBDINGS, Peter, J.; SmithKline Beecham, Intellectual
Property, Mundells, Welwyn Garden City, Hertfordshire
AL7 1EY (GB).

(81) Designated States: JP, US, European patent (AT, BE, CH, DE,
DK, ES, FR, GB, GR, JE, IT, LU, MC, NL, PT, SE).

Published

With international search report.

(54) Title: HETEROCYCLIC UREA DERIVATIVES AS 5HT 2 c AND 5HT2B ANTAGONISTS

2 3

(57) Abstract

A compound of formula (I) or a salt thereof wherein: P is a quinoline, isoquinoline, or a 5- or 6-membered aromatic heterocyclic ring
containing up to three heteroatoms selected from nitrogen, oxygen or sulphur, J is a ring system selected from quinoline, tetrahydroquinoline,
indoline, indazole, benzothiophene, indene, indane, benzothiazole or benzofuran; R 1 is hydrogen, Ci-6alkyl, halogen, NR 5 R 6 or OR 7 , where
R 5 , R 6 and R 7 are independently hydrogen or Ci-6alkyl; and R 2 and R 3 are independently hydrogen or Ci-talkyl. R 4 is Ci-ealkyL OR 8 or
halogen, where R 8 is hydrogen or Ci-6alkyl; and n is 1 or 2; provided that: when P is other than pyridyL J is not indoline, P and J are
not both 6-methoxy quinoline, 8-hydroxy quinoline or 2-methyl quinoline, when J is quinoline or 2-methyl quinoline, P is not 2-thiazolyl,
when P and J are both quinoline and R 1 , R 2 and R 3 are all hydrogen, R 4 is not hydrogen or 6-methoxy. Compound of formula (I) and
their pharmaceutically acceptable salts have 5HT2C receptor antagonist activity and are believed to be of potential use in the treatment or
prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic
attacks, withdrawal from drug abuse, schizoprenia and/or disorders associated with spinal trauma and/or head injuries.

FOR THE PURPOSES OF INFORMATION ONLY

Codes used to identify States party to die PCT on the front pages of pamphlets publishing international
applications under the PCT.

AT

Austria

GB

United Kingdom

MR

Mauritania

AD

Australia

GE

Georgia

MW

Malawi

BB

Barbados

GN

Guinea

NE

Niger

BE

Belgium

GR

Greece

NL

Netherlands

BF

Burkina Faso

HU

Hungary

NO

Norway

BG

Bulgaria

IE

Ireland

NZ

New Zealand

BJ

Benin

IT

Italy

PL

Poland

BR

Brazil

JP

Japan

PT

Portugal

BY

Belarus

KE

Kenya

RO

Romania

CA

Canada

KG

Kyrgystan

RU

Russian Federation

CF

Central African Republic

KP

Democratic People's Republic

SD

Sudan

CG

Congo

of Korea

SE

Sweden

CH

Switzerland

ICR

Republic of Korea

SI

Slovenia

CI

Cote d'lvoire

KZ

Kazakhstan

SK

Slovakia

CM

Cameroon

LI

Liechtenstein

SN

Senegal

CN

China

LK

Sri Lanka

TD

Chad

CS

Czechoslovakia

LU

Luxembourg

TG

Togo

CZ

Czech Republic

LV

Latvia

TJ

Tajikistan

DE

Germany

MC

Monaco

TT

Trinidad and Tobago

DK

Denmark

MD

Republic of Moldova

UA

Ukraine

ES

Spain

MG

Madagascar

US

United States of America

FI

Finland

ML

Mali

uz

Uzbekistan

FR

France

MN

Mongolia

VN

Viet Nam

GA

Gabon

WO 94/14801

PCT/EP93/03666

HETEROCYCLIC UREA DERIVATIVES AS 5HT2C AND 5HT2B ANTAGONISTS

This invention relates to compounds having pharmacological activity, to a process
for their preparation, to compositions containing them and to their use in the treatment of
5 mammals.

WO 92/051 70 describes certain urea derivatives which are described as possessing
5HTic receptor antagonist activity. Quinolyl urea derivatives are also disclosed in J. Med.
Chem., 1992, 35, 252, J. Het. Chem., 1968, 5, 371 and DE 2847792. The 5HT 1C
receptor has recently been reclassified as the 5HT 2 c receptor [P. Hartig et al., Trends in

1 0 Pharmacological Sciences (TIPS ) 1 993] .

A structurally distinct class of compounds has now been discovered, which have
been found to have 5HT2C receptor antagonist activity. Certain compounds of the
invention also show 5HT2B receptor antagonist activity, the 5HT2B receptor being
previously known as the fundus receptor [P.Hartig et al., Trends in Pharmacological

15 Sciences (TIPS) 1993]. 5HT 2 c /5HT2B receptor antagonists are believed to be of
potential use in the treatment of CNS disorders such as anxiety, depression, obsessive
compulsive disorders, migraine, anorexia, Alzheimers disease, sleep disorders, bulimia,
panic attacks, withdrawal from drug abuse such as cocaine, ethahol, nicotine and
benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or

20 head injury such as hydrocephalus.

In a first aspect the present invention therefore provides a compound of formula (I)

or a salt thereof:

2 3

R R

25

wherein:

P is a quinoline, isoquinoline, or a 5- or 6-membered aromatic heterocyclic ring containing

up to three heteroatoms selected from nitrogen, oxygen or sulphur;
30 J is a ring system selected from quinoline, tetrahydroquinoline, indoline, indazole,

benzothiophene, indene, indane, benzothiazole or benzofuran;

r! is hydrogen, Ci_6 alkyl, halogen, NR 5 R 6 or OR 7 , where R 5 , R 6 and R 7 are

independently hydrogen or C\.(> alkyl; and

r2 and R 3 are independently hydrogen or C\_6 alkyl.
35 R 4 is Ci_6 alkyl, OR 8 or halogen, where R 8 is hydrogen or C\.$ alkyl; and

- 1 -

WO 94/14801

PCT/EP93/03666

n is 1 or 2;
provided that

• when P is other than pyridyl, J is not indoline,

• P and J are not both 6-methoxy quinoline, 8-hydroxy quinoline or 2-methyl quinoline,
5 • when J is quinoline or 2-methyl quinoline P is not 2-thiazolyl,

• when P and J are both quinoline and R 1 , R 2 and R 3 are all hydrogen, R 4 is not
hydrogen or 6-methoxy.

Ci_ 0 alkyl groups, whether alone or as pan of another group, can be straight chain
or branched.

10 The urea moiety can be attached to a carbon or, when present, a suitable nitrogen

atom of the ring P, preferably it is attached to a carbon atom. The urea moiety can be
attached to any suitable carbon atom of the aromatic 6-membered ring of the ring J.

Suitable moieties when the ring P is a 5-membered aromatic heterocyclic ring
include isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl. Suitable moieties when the ring P
15 is a 6-membered aromatic heterocyclic ring include, for example, pyridyl, pyrirnidyl or

pyrazinyl. When P is a quinoline or isoquinoline residue, the urea moiety can be attached at
any position of the ring, preferably to the 4-position.

The ring J can be quinoline, tetrahydroquinoline, indoline, indazole, benzothiophene,
indene, indane, benzothiazole or benzofuran. Preferably J is 3- or 6-quinoline, 5-indoline,
20 5-benzothiophene, 5-indene, 5-indane, 5-indazole or 5-benzofuran. Most preferably J is 5-
benzothiophene.

The rings P and J can be substituted at any suitable position.
Preferably P is 3-pyridyl.
Preferably R 1 , R 2 and R 3 are all hydrogen.
25 R 4 groups can be attached to any suitable carbon atom of the ring J or, when R 4 is

Ci_5alkyl, to a nitrogen atom if present. When n is 2, the resulting R 4 groups can be the
same or different.

Preferred compounds of formula (I) include:
N-5-(Benzo[b]thienyl)-N'-(3-pyridyl)urea
30 N-(5-Indenyl)-N'-(3-pyridyl) urea

N-(l,l-Dimethyl-5-indenyl)-N'-(3-pyridyl) urea
N-(5-Benzothiazolyl)-N'-(3-pyridyl) urea
N-(5-Benzofuryl)-N'-(3-pyridyl) urea
N-(l-Methyl-5-indolinyl)-N'-(3-pyridyl)urea
35 N-(3-Pyridyl)-N-(3-quinolinyl) urea
N-(3-Pyridyl)-N'-(6-quinolinyl) urea
N-(2-Methyl-4-quinolinyl)-N'-(3-pyridyl) urea
N-5-(Benzo[b]thienyl)-N'-(2-methyl-4-quinolyl)urea

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WO 94/14801

PCT/EP93/03666

N-(3-Pyridyl)-N-(5-quinolinyl)urea
N-(3-Pyridyl)-N'-(8-quinolinyl) urea
N-(5-Indanyl)-N'(3-pyridyl) urea

N-(3-PyiWyl)-N , -(6-(l-methyl-1^3Atetrahydro)quinolinyl)urea
5 N-( 1 -methyl-5-indazolyl)-N'-(3-pyridyl)urea

N-(3-Methyl-5-benzo[b]thienyl)-N'-(3-pyridyl)urea

N-(2-Methyl-5-benzo[b]thienyl)-N'-(3-pyridyl)urea

N-(4-Methyl-5-benzo[b]thienyl)-N'-(3-pyridyl)urea

N-(5-Benzo[b]thienyl)-N'-(3-methyl-5-isoxazolyl)urea
10 N-(5-Benzo[b]thienyl)-N'-(3-methyl-5-isothiazolyl)urea

and pharmaceutically acceptable salts thereof.

The compounds of the formula (I) can form acid addition salts with acids, such as

conventional pharmaceutically acceptable acids, for example maleic, hydrochloric,

hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and
15 methanesulphonic.

Compounds of formula (I) may form solvates such as hydrates, and the invention

also extends to these forms. Certain compounds of formula (I) may also form N-oxides or

S-oxides. When referred to herein, it is understood that the term 'compound of formula (I)'

also includes these forms.
20 Certain compounds of formula (I) are capable of existing in stereoisomeric forms

including enantiomers and the invention extends to each of these stereoisomeric forms and

to mixtures thereof including racemates. The different stereoisomeric forms may be

separated one from the other by the usual methods, or any given isomer may be obtained by

stereospecific or asymmetric synthesis. Certain compounds of formula (I), for example
25 those where R 2 and/or R 3 are hydrogen, may exist tautomerically in more than one form.

The invention extends to these and any other tautomeric forms and mixtures thereof.

In a further aspect, the present invention provides a process for the preparation of a

compound of formula (I) or a pharmaceutically acceptable salt thereof, which process

comprises:

30 the coupling of a compound of formula QI);

with a compound of formula (III);

35

WO 94/14801

PCT/EP93/03666

B kL)~~ (R4)n

wherein P and n are as defined in relation to formula (I), A and B contain the appropriate
functional group(s) necessary to form the moiety, -NR 2 'CONR 3 ' when coupled, the
5 variables R 1 ', R 2 ', R 3 ' and J' are R 1 , R 2 , R 3 , and J respectively, as defined in formula (I),
or groups convertible thereto, and thereafter optionally and as necessary and in any
appropriate order, converting any R 1 ', R 2 ', R 3 ' and J', when other than R 1 , R 2 , R 3 and J
respectively to R 1 , R 2 , R 3 and J, interconverting R 1 , R 2 , R 3 and J and forming a
pharmaceutically acceptable salt thereof.
10 Suitable examples of groups A and B include:

(i) A is -N=C=0 and B is -NHR 3 ',

(ii) A is -NR 2 'COL and B is -NHR 3 ',
(hi) A is -NHR 2 ' and B is NR 3 'COL,

15 (iv) A is NHR 2 ' and B is -N=C=0 or '
(v) A is halogen and B is -NR 3 CONHR 2 '

wherein R 2 ' and R 3 ' are as defined above and L is a leaving group. Examples of suitable
leaving groups L include halogen such as chloro, bromo, imidazole or phenoxy or
20 phenylthio optionally substituted for example with halogen.

When A is -N=C=0 and B is NHR 3 ' or when A is NHR 2 ' and B is -N=C=0 the
reaction is suitably carried out in an inert solvent for example dichloromethane or toluene at
ambient temperature.

When A is -NR 2 COL and B is NHR 3 ' or when A is -NHR 2 ' and B is -NR 3 COL,
25 the reaction is suitably carried out in an inert solvent such as dichloromethane at ambient
temperature optionally in the presence of a base, such as triethylamine or in
dimethylformamide at ambient or elevated temperature.

When A is halogen and B is NR 3 'CONHR 2 ', the reaction is suitably carried out in
an inert solvent such as toluene at elevated temperature, optionally in the presence of a
30 base.

Interconversions of compounds of formula (I) to further compounds of formula (I)
can be carried out using standard procedures. Suitable examples of groups R 1 and R 4
which are convertible to R 1 and R 4 alkyl groups respectively, include acyl groups which are
introduced conventionally and may be converted to the corresponding alkyl group by
35 conventional reduction, such as using sodium borohydride in an inert solvent followed by
hydrogenolysis in an inert solvent. Hydrogen substituents may be obtained from
alkoxycarbonyl groups which may be converted to hydrogen by hydrolysis and

-4-

WO 94/14801

PCT/EP93/03666

decarboxylation. When R 4 is hydroxy it is preferably protected in the compound of formula
(II) as, for example, ben2yl which is removed by hydrogenation.

When R 2 is C]_6 alkyl and R 3 is hydrogen it is possible to introduce a
Ci_6 alkyl group at the R 3 position by conventional alkylation using 1 molar equivalent of a
5 Ci_6 alkyl halide and 1 molar equivalent of a suitable base in an inert solvent. Suitable

examples of a group R 2 ' and R 3 ' which is convertible to R 2 and R 3 , include alkoxycarbonyl
and benzyl or para-methoxybenzyl which are converted to R 2 and R 3 is hydrogen using
conventional conditions.

r1 halo and R 4 halo may be introduced by selective halogenation of the ring P or
10 the benzene ring of J ring respectively using conventional conditions.

It should be appreciated that it may be necessary to protect any hydrogen variables
which are not required to be interconverted. Suitable protecting groups and methods for
their attachment and removal are conventional in the art of organic chemistry, such as those
described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981).
15 It should be appreciated that it is preferred that groups R 1 to R 4 are introduced

before coupling compounds of formula (II) and (lit).

Compounds of formula (II) in which A is NHR 2 ' are known compounds or can be
prepared analogously to known compounds, see, for example, WO 92/05170 .

Compounds of formula (II) in which A is -N=C=0 may be prepared by treating a
20 compound of formula (II) in which :

i) A is amino, with phosgene or a phosgene equivalent, in the presence of
excess base in an inert solvent.

ii) A is acylazide (i.e. CON3), via the nitrene, by thermal rearrangement using
conventional conditions (ref L.S. Trifonov ej aL Helv. Chim. Acta 1987 7_Q 262).

25 iii) A is CONH2> v * a ^ e nitrene intermediate using conventional conditions.

Compounds of formula (II) in which A is NR 2 'COL may be prepared by reacting a
compound of formula (II) in which A is NHR 2 ' with phosgene or a phosgene equivalent in
an inert solvent, at low temperature, if necessary in the presence of one equivalent of a base
such as triethylamine.

30 Compounds of formula (III) may be prepared according to known methods or

analogous to known methods. For example compounds of formula (HI) where B is NHR 3
where R 3 is hydrogen may be prepared by conventional reduction of the corresponding 5-
nitro compounds such as those outlined in description 2 to 6.

Compounds of formula (II) in which A is halogen and R 4 ' is hydrogen are

35 commercially available.

WO 94/14801

PCT/EP93/03666

Compounds of formula (III) in which B is -N=C=0, NHR 3 ', NR^COL and
NR 3 CONHR 2 ' can be prepared using procedures analogous to those outlined for
compounds of formula (II) above.

Examples of phosgene equivalents include triphosgene, carbonyldiimidazole,
5 phenyl chloroformate and phenyl chorothioformate.

Pharmaceutically acceptable salts can be prepared conventionally by reaction with
the appropriate acid or acid derivative. N-oxides and S-oxides can be formed
conventionally by reaction with hydrogen peroxide or percarboxylic acids.

Certain intermediates of formula (III) form a further aspect of the invention.
10 Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT2C

receptor antagonist activity and are believed to be of potential use in the treatment or
prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders,
Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse,
schizophrenia and/or disorders associated with spinal trauma and/or head injuries.
1 5 Thus the invention also provides a compound of formula (I) or a pharmaceutically

acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or
prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders,
Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse,
schizophrenia and/or disorders associated with spinal trauma and/or head injuries.
20 The present invention also provides a pharmaceutical composition, which

comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.

In another aspect, the invention provides the use of a compound of formula (IA) or
a salt thereof:

25

2 3

R R

I I

(IA)

30 wherein:

P is a quinoline, isoquinoline, or a 5- or 6-membered aromatic heterocyclic ring containing
up to three heteroatoms selected from nitrogen, oxygen or sulphur;
J is a ring system selected from quinoline, tetrahydroquinoline, indoline, indazole,
benzothiophene, indene, indane, benzothiazole or benzofuran;
35 R 1 is hydrogen, C\.$ alkyl, halogen, NR 5 R 6 or OR 7 , where R 5 , R 6 and R 7 are

-6-

WO 94/14801

PCT/EP93/03666

independently hydrogen or C\.^ alkyl; and
R2 and are independendy hydrogen or Cj.g alkyl.
R 4 is Ci_6 alkyl, OR 8 or halogen, where R 8 is hydrogen or Cj.g alkyl; and
n is 1 or 2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament
5 for the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive
compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks,
withdrawal from drug abuse, schizophrenia and/or also disorders associated with spinal
trauma and/or head injuries, in particular the treatment or prophylaxis of anxiety and
depression.

10 The invention further provides a method of treatment or prophylaxis of anxiety,

depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep
disorders, bulimia, panic attacks, withdrawal from drug abuse, schizophrenia and/or
disorders associated with spinal trauma and/or head injuries, in mammals including humans,
which comprises administering to the sufferer a therapeutically effective amount of a

15 compound of formula (I A) or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition of the invention, which may be prepared by
admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for
oral, parenteral or rectal administration and, as such, may be in the form of tablets,
capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders,

20 injectable or infusible solutions or suspensions or suppositories. Orally administrable
compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may
contain conventional excipients, such as binding agents, fillers, tabletting lubricants,
disintegrants and acceptable wetting agents. The tablets may be coated according to

25 methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily
suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product
for reconstitution with water or other suitable vehicle before use. Such liquid preparations
may contain conventional additives such as suspending agents, emulsifying agents,

30 non-aqueous vehicles (which may include edible oils), preservatives, and, if desired,
conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are prepared utilising a
compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
The compound, depending on the vehicle and concentration used, can be either suspended

35 or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for
injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents
are dissolved in the vehicle. To enhance the stability, the composition can be frozen after

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WO 94/14801

PCT/EP93/03666

filling into the vial and the water removed under vacuum. Parenteral suspensions are
prepared in substantially the same manner, except that the compound is suspended in the
vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile
5 vehicle. Advantageously, a surfactant or wetting agent is included in the composition to
facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to
60% by weight, of the active material, depending on the method of administration.

The dose of the compound used in the treatment of the aforementioned disorders
10 will vary in the usual way with the seriousness of the disorders, the weight of the sufferer,
and other similar factors. However, as a general guide suitable unit doses may be 0.05 to
1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may
be administered more than once a day, for example two or three a day, so that the total
daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a
15 number of weeks or months.

The following Examples illustrate the preparation of compounds of the invention.

WO 94/14801

PCT/EP93/03666

Description 1

5-Nitrobenzo[b]thiophene (Dl)

5 Ethyl 5-nitrobenzo[b]thiophenecarboxylate was prepared and hydrolysed to the

corresponding acid as described by S. Rossi and R. Trave (FI Farmaco - Ed. Sci., 1960, 15,
396). 5-Nitrobenzo[b]thiophenecarboxylic acid (4.32 g, 19.4 mmol) was heated with
copper powder (1.2 g, activated by heating for several hours at 160°C in vacuo) in
quinoline (25 ml) at 180-190°C for 2h. After cooling, the mixture was diluted with ether
10 and washed thoroughly with 5N hydrochloric acid. The organic phase was dried and

evaporated, and the crude product was recrystallised from ether to give the tide compound
(3.24 g, 77%), m.p. 142-145°C.

NMR (CDC1 3 ) 8: 7.52 (1H, d, J 6), 7.68 (1H, d, J 6), 8.00 (1H, d, J 8), 8.22 (1H, dd,
15 J 8, 2), 8.74(lH,d, J2).

Description 2

5-Aminobenzo[b]thiophene (D2)

20 Hydrazine hydrate (85% aqueous solution, 2 ml) was added portionwise to a suspension of
Raney nickel (0.25 g) and 5-nitrobenzo[b]thiophene (Dl) (1.79 g, 10 mmol) in ethanol
(50 ml), with shaking. After 0.5h at room temperature a further portion (0.5 ml) of
hydrazine solution was added and the mixture was heated under reflux for 0.5h. The
cooled reaction mixture was filtered through kieselguhr and the filtrate was evaporated in

25 vacuo. The residue was recrystallised from ether/petrol to give the title compound (1.18 g,
79%), m.p. 70-72°C.

NMR (CDC13) 6: 6.79 (1H, dd, J 8, 2), 7.10 (1H, d, J 2), 7.15 (1H, d, J 6), 7.39 (1H, d
J 6), 7.63 (1H, d, J 8).

30

Description 3
5-Aminoindene (D3)

5-Nitroindene was prepared by the method of P. Wan et al. (J. Org. Chem., 1989, 54,
35 1354), but with chlorobenzene replacing toluene for the final dehydration step. A mixture
of 5-nitroindene (0.76 g, 4.7 mmol), anhydrous tin (II) chloride (5.4 g) and ethanol
(100 ml) was heated under reflux for 3.5 h, then poured onto ice and extracted with
dichloromethane/THF. The aqueous phase was basified with dilute ammonia and extracted

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WO 94/14801

PCT/EP93/03666

again with dichloromethane/THF. The organic extract was filtered through kieselguhr,
dried and evaporated, and the residue was dissolved in dichloromethane, filtered again and
evaporated to give the title compound (0.44 g, 71%) as a gummy solid.

5 NMR (CDC13) 5: 3.30 (2H), s), 3.52 (2H, broad s), 6.55 (2H, m), 6.78 (2H, m), 7.24
(lH,d,J7).

Description 4

l,l-DimethyI-5-aminoindene (D4)

10

l,l-Dimethyl-5-nitroindene was prepared by the method of Wan et al, as modified in
Description 3, using 3,3-dimethyl-6-nitro-l-indanone (J. G. Smith and M. P. and M. P.
Massicotte, Org. Prep. Proc. Int., 1978, 10, 123) as starting material. A mixture of 1,1-
dimethyl-5-nitroindene (0.47 g, 2.5 mmol) tin (II) chloride (2.87 g) and ethanol (50 ml) was
15 heated under reflux overnight. The mixture was poured onto ice and extracted with

dichloromethane. The aqueous phase was then basified with dilute ammonia and extracted
with dichloromethane/THF. The organic extract was washed with water, dried and
evaporated to give the title compound (0.24 g, 61%) as an oil.

20 NMR (CDC13) 8: 1.28 (6H, s), 6.35 (1H, d, J 6), 6.52 (1H, d, J 6), 6.55 (1H, dd, J
8,2), 6.68 (1H, d, J 2), 7.09 (1H, d, J 8).

Description 5

5-Aminobenzothiazole (D5)

25

5-Nitrobenzothiazole was prepared by the method of I. Spieler and B. Prijs (Helv. Chim.
Acta., 1950, 33, 1429). To a suspension of 5-nitrobenzothiazole (0.13 g, 0.72 mmol) and
Raney nickel (0.025 g) in ethanol (5 ml) was added hydrazine hydrate (0.25 ml) in small
portions. The mixture was then heated under reflux for 75 mins, cooled, filtered through
30 Kieselguhr and evaporated. The residue was chromatographed on silica gel (7 g) eluted
with 2% methanol/dichloromethane, to give the title compound (27 mg, 25%).

NMR (CDC13) 5: 3.9 (2H, broad), 6.88 (1H, d, J 8), 7.41 (1H, s), 7.71 (1H, d, J 8),
8.92 (1H, s).

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Description 6
5-Aminobenzofuran (D6)

5 5-Nitobenzofuran was prepared from 5-nitro-2-benzofnrancarboxylic acid by the method of
H. Erlenmeyer et al. (Helv. Chim. Acta, 1948, 21, 75). The nitrobenzofuran (0.24 g, 1.47
mmol) was reduced with Raney nickel (0.04 g) and hydrazine hydrate (85% aq. solution,
0.4 ml) in ethanol (10 ml) according to the procedure of Description 2. Further hydrazine
hydrate and Raney nickel were added and reflux continued as required to obtain complete
10 reaction. The initial crude product was taken up in dichloromethane, filtered and
evaporated to give the title compound (0.16 g, 82%) as a dark, rather unstable oil.

NMR (CDC13) 8: 3.3 (2H, broad), 6.61 (1H, d, J 2), 6.68 (1H, d, J 8), 6.85 (1H, s),
7.32 (1H, d, J 8), 7.55 (1H, d, J 2).

15

Description 7

l-Methyl-5-nitroindoIine (D7)

To a stirred suspension of sodium hydride (0.35g, 12.15 mmol) in dimethylformamide
20 (5 ml) at 0°C, under nitrogen, was added 5-nitroindoline (2g, 12.19 mmol) in
dimethylformamide. After stirring for 0.5h, iodomethane (0.8 ml; 12.9 mmol) in
dimethylformamide (10 ml) was added, and stirring was continued for 3h. The reaction
mixture was then quenched with water, and poured onto excess water with stirring.
Filtration afforded the tide compound (2.18g, 99%).

25

NMR (CDC13) 5: 2.91 (3H, s), 6.27 (1H, d), 7.89 (1H, m), 8.09 (1H, dd).

Description 8

5-Amino-l-methyIindoIine (D8)

A mixture of the nitroindoline (D7, 1.5g, 8.4 mmol) and 5% palladium on charcoal in
ethanol (70 ml) was hydrogenated at 60 p.s.i. (4.14xl0 5 Pa) at room temperature for 2h.
Removal of the catalyst by filtration followed by evaporation of the solvent gave the title
compound (1.27g, 98%).

NMR (CDC13) 8: 2.67 (3H, s), 6.38 (1H, d), 6.5 (1H, d), 6.59 (1H, s).

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Description 9

3-Pyridyl Isocyanate (D9)

The title compound was prepared using a procedure similar to that described by L.S.
5 Trifonov elal, Helv. Chim.Acta, 1987, 7_Q, 262.

Description 10

6-Trifluoroacetamidoquinoline (D10)

10 To a solution of 6-aminoquinoline (9.9g, 69 mmol) in chloroform (200 ml) was added
triethylamine (1 1 ml, 79 mmol) followed by trifluoroacetic anhydride (1 1 ml, 79 mmol)
dropwise with stirring. The mixture was stirred at ambient temperature for 2 hrs and
eventually set solid. The residue was partitioned between 5% methanol/chloroform
(1000 ml) and water (500 ml). The organic layer was separated and dried (Na2SC>4),

15 filtered and evaporated to dryness. This gave the title compound (16.5 g, 100%) as a gum.

Description 11

6-Trifluoroacetamido-l,2,3,4-tetrahydroquinoline (Dll)

20

Nickel (I) chloride hexahydrate (3.3 g, 14 mmol) was added to a solution of 6-
trifluoroacetamidoquinoline (D9) (16.5 g, 69 mmol) in methanol (250 ml) at ambient
temperature with stirring. Sodium borohydride (13.4 g, 350 mmol) was then added
portionwise over 20 mins resulting in a large evolution of gas. The mixture was stirred for

25 a further 1 V4 hrs then concentrated in vacuo. The residue was treated with 5N hydrochloric
acid (500 ml) and left to stand for 20 mins. The mixture was basified with 40% sodium
hydroxide and extracted with dichloromethane chloride (2 x 400 ml). The organic layer
was separated and dried (Na2SC>4), filtered and evaporated to dryness. Flash
chromatography on TLC silica gel eluting with 0-4% methanol/dichloromethane gave the

30 title compound (6.5g, 39%).

NMR (CDC1 3 ) 8 : 1 .95 (2H, t, J 8), 2.75 (2H, t, J 8), 3.31 (2H, t, J 8), 6.44 (1H, d, J
11), 7.08 (1H, d, J 12), 7.15 (1H, s), 7.60-7.78 (1H, br s).

35

Description 12

l-Methyl-6-trifluoroacetamido-l,23,4-tetrahydroquinoline (D12)

6-Trifluoroacetamido-l,2,3,4-tetrahydroquinoline (Dll) (1.29g, 5.3 mmol) and 40%
40 aqueous formaldehyde solution (4.0 ml, 53 mmol) was hydrogenated at atmospheric

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pressure and ambient temperature in ethanol (80 ml) over 10% palladium/charcoal catalyst
(0.5g) for 20 hrs. The mixture was filtered through kieselguhr and the filtrate evaporated to
dryness. Flash chromatography of the residue on TLC silica gel eluting with 0-2%
methanol/dichloromethane gave the title compound (D12) (1.21g, 89%) as an oil.

5

NMR (CDC1 3 ) 5 : 1.91-2.03 (2H, m), 2.75 (2H, t, J 7), 2.89 (3H, s), 3.22 (2H, t, J 7),
6.51 (1H, d, J 10), 7.14-7.21 (2H, m), 7.60-7.72 (1H, br s)

Description 13

10 6-Amino-l-methyl-l,23,4-tetrahydroquinoline (D13)

1 -Methyl-6-trifluoroacetamido-l, 2,3,4- tetrahydroquinoline (D12) (1.21g, 4.7 mmol) in
ethanol (50 ml) was heated under reflux with 10% aqueous sodium hydroxide solution
(4 ml, 9.4 mmol) for 4 hrs. The mixture was evaporated to dryness and the residue
15 partitioned between water and dichloromethane. The organics were separated and dried
(Na2SC>4), filtered and evaporated to dryness to give the title compound (D13) (0.74g,
97%) as an oil.

NMR (CDCI3) 8 : 1.91-2.03 (2H, m), 2.72 (2H, t, J 7), 2.80 (3H, s), 3.10 (2H, t, J 7),
20 3.20-3.32 (2H, br s), 6.40-6.52 (3H, m).

Example 1

N*-5-(Benzo[b]thienyl)-N'-(3-pyridyl)urea

25 A suspension of l,l'-carbonyldiimidazole (1.295 g, 8 mmol) in dichloromethane (40 ml)
was cooled to 0°C, and a solution of aminobenzothiophene (D2) (1.12 g, 7.5 mmol) in
dichloromethane (40 ml) was added. The mixture was stirred at 0.°C for 15 min, then
solvent was removed in vacuo and replaced by dimethylformamide (30 ml). 3-
aminopyridine (0.705 g, 7.5 mmol) was added in dimethylformamide (10 ml) and the

30 mixture was heated at approx. 120°C for lh. After cooling the mixture was poured into
water and the precipitate was filtered off, washed with water and dried.
The crude product was recrystallised from dimethylsulphoxide/water in two crops, the
second crop being desired product. This material was recrystallised again in the same
manner to give the title compound (1.03 g, 51%), m.p. 217°C (decomp.).

35

NMR (D6-DMSO) 8: 7.34 (1H, m), 7.38 (1H, dd, J 10,2), 7.62 (1H, d, J 6), 7.74 (1H, d,
J 6), 7.90 (1H, d, J 10), 7.98 (1H, d, J8), 8.13 (1H, d, J 2), 8.21 (1H, broad s), 8.63 (1H,
broad s), 8.91 (2H, d, J 8).

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Found: C, 62.47; H, 4.13; N, 15.45%

C14H1 1N3OS requires C, 62.43; H, 4.12; N, 15.60%

Found: M+ 269 C14H11N3OS requires 269.

Example 2

N-(5-Indenyl)-N'-(3-pyridyl) urea

A solution of nicotinoyl azide (0.59 g, 4 mmol) in toluene (10 ml) was heated under reflux
for 2h, then cooled and a solution of aminoindene (D3) (0.44 g, 3.36 mmol) in

10 dichloromethane (10 ml) was added. The mixture was stirred overnight at room

temperature. Addition of a little petrol (bp. 60-80°C) caused formation of a precipitate,
which was filtered off and washed with petrol. The crude product was chromotographed
on silica gel (50 g) eluted with 5% methanol/dichloromethane. Eluted product was
recrystallised from dichloromethane/petrol to give pure title compound E2 (0.35 g, 41.5%),

15 m.p. 161-163°C.

NMR (D6-DMSO) 8: 3.37 (2H, s), 6.73 (1H, d, J 6), 6.92 (1H, d, J 6), 7.20 (1H, d, J 7),
7.32 (1H, m), 7.39 (1H, d, J 7), 7.61 (1H, s), 7.69 (1H, d, J 7), §.19 (1H, d, J 5), 8.61 (1H,
s), 8.78 (1H, s), 8.84 (1H, s).

20

Found: M+251 C^H^^O requires 251.

Example 3

N-(l,l-Dimethyl-5-indenyl)-N'-(3-pyridyI) urea

25

A solution of nicotinoyl azide (0.25 g, 1.7 mmol) in toluene (5 ml) was heated under reflux
for 2h, then cooled and a solution of aminoindene (D4) (0.24 g, 1.5 mmol) in
dichloromethane (5 ml) was added. The mixture was stirred overnight at room
temperature, then dichloromethane, was removed under vacuum and petrol was added,
30 causing the product to separate as an oil. Solvent was removed and the oil was triturated
with ether. Evaporation in vacuo gave a solid foam. The crude product was
chromatographed on silica gel (12.5 g) eluted with 2 - 4% methanol/dichloromethane.
Eluted product was recrystallised from dichloromethane/petrol to give the title compound
(0.18 g, 43%), mp. 150-155°C.

35

NMR (CDC13) 8: 1.24 (6H, s), 6.35 (1H, d, J 6), 6.49 (1H, d, J 6), 7.06 (1H, d, J 8),
7.18 (2H, m), 7.29 (1H, s), 7.80 (1H, s), 8.02 (1H, d, J 8) 8.16 (1H, s), 8.18 (1H, d, J 5),
8.34 (1H, s).

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Found: C, 72.41; H, 6.28; N, 14.91%
C17H17N3O requires C, 73.10; H, 6.13; N, 15.04%
Found: M + 279 Ci7H 17 N 3 0 requires 279.

5

Example 4

N-(5-Benzothiazolyl)-N'-(3-pyridyl) urea

A solution of nicotinoyl azide (29 mg, 0.2 mmol) in toluene (1 ml) was heated under reflux
10 for 2h, then cooled and a solution of aminobenzo-thiazole (D5) (27 mg, 0.18 mmol) in
dichloromethane (1 ml) was added. The mixture was stirred at room temperature for lh,
then the precipitated product was filtered off, washed with petrol and dried in vacuo to give
the tide compound (31 mg, 64%), mp 206-211 °C.

15 NMR (D6-DMSO) 5: 7.35 (1H, m), 7.50 (1H, d, J 8), 7.99 (1H, d, J 8), 8.08 (1H, d, J 8),
8.21 (1H, d, J 5), 8.35 (1H, s), 8.64 (1H, s), 8.98 (1H, s), 9.10 (1H, s), 9.49 (1H, s).

HPLC analysis indicates 89.7% purity.
Found: M + 270 Ci3H ]0 N4OS requires 270.

20

Example 5

N-(5-Benzofuryl)-N'-(3-pyridyl) urea

A solution of nicotinoyl azide (0.19 g, 1.28 mmol) in toluene (5 ml) was heated at 100°C
25 for 2H, then cooled and a solution of 5-aminobenzofuran (D6) (0. 1 6 g, 1.2 mmol) in

dichloromethane (5 ml) was added. The mixture was stirred overnight at room temperature
and the precipitated product was filtered off, washed with petrol and dried. The crude
product was recrystallised from dichloromethane/methanol to give the title compound
(0.17 g, 56%), mp. 159-162°C.

30

NMR (D6-DMSO) 5: 6.94 (1H, d, J 2), 7.30 (2H, m), 7.52 (1H, d, J 8), 7.83 (1H, d, J 2),
7.95 (1H, s), 7.97 (1H, d, J 2), 8.20 (1H, s), 8.62 (1H, s), 8.86 (2H, d, J 5).

Found: C, 65.78; H, 4.41; N, 16.60%; C^Hn^C^ requires C, 66.40; H, 4.38; N,
35 16.59%.

Found: M+253; C14H11N3O2 requires 253.

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Example 6

N-(l-Methyl-5-indolinyl)-N'-(3-pyridyl)urea dihydrochloride

To a solution of the aminoindoline (D8) (1.27g; 8.58 mmol) in dry dichloromethane (20 ml)
5 at 0°C was added triethylamine (1.3 ml). After stirring for 0.5h, a 12.5% solution of
phosgene in toluene (10.2 ml, 11.79 mmol) was added and stirring continued for 0.5h.
Triethylamine (2.63 ml) was then added and after another 0.5h, a solution of 3-
aminopyridine (0.8g; 8.5 mmol) in dry dichloromethane (10 ml) added and the reaction
mixture left for 2h at room temperature. Several drops of aqueous sodium hydroxide in

10 water (5 ml) was added to the reaction mixture which was vigorously stirred for 0.5h. The
reaction mixture was diluted with water and extracted with dichloromethane. The
combined organic extracts were washed with brine, dried over sodium sulphate and
evaporated to dryness. Chromatography on silica using dichloromethane as eluant afforded
the title compound (1.39g, 60%) which was converted to the dihydrochloride salt using

15 hydrogen chloride in ether/ethanol. mp 252°C.

NMR (D6 DMSO) 6: 3.21 (3H, s), 3.32 (2H, m), 4 (2H, m), 7.42 (4H, m), 7.9 (1H,
m), 8.35 (2H, m), 9.08 (1H, s).
m/z (E.I.): 268 (M+)

20

Example 7

N-5-(Benzo[b]thienyl)-N'-(2-methyl-4-quinolyl) urea

The title compound was prepared from 2-methyl-4-aminoquinoline, 1,1-carbonyl
25 diimidazole and 5-aminobenzo[b]thiophene (D2) in 46% yield, m.p. 110 - 1 15°C.

NMR (DMSO) 5: 2.61 (3H, s), 7.39 - 7.48 (2H, m), 7.58 - 7.63 (1H, t, J = 6), 7.7 - 7.8
(2H, m), 7.89 - 7.98 (2H, m), 8.17 - 8.21 (3H, m), 9.22 (1H, s), 9.45 (1H, s).

30 Example 8

N-(3-Pyridyl)-N/-(6-quinolinyl) urea dihydrochloride

A solution of 6-aminoquinoline (0.5g, 0.30 mM) in dichloromethane (4.0 ml) was added
dropwise to a solution of 3-pyridyl isocyanate (D9), prepared from 3-pyridinecarbonyl azide
35 (0.55g, 0.37 mM) in toluene (5.0 ml), at room temperature. The reaction mixture was
stirred for l8h, then cooled, and the precipitate collected by filtration to give the crude
product (0.91g; 99%). This was dissolved in hot ethanol and ethereal hydrogen chloride
added to afford the tide compound as its dihydrochloride salt (l.Og, 85%) m.p. 215-220°.

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NMR (d 6 -DMSO) 8: 7.01 (1H, t, J=6Hz), 7.20-7.38 (2H, m), 7.41-7.54 (2H, m), 7.88-
8.03 (1H, m), 8.28-8.39 (1H, m), 8.45-8.60 (1H, m), 9.06-9.16 (1H, m), 9.71 (1H, s) 10.55
(1H, s).

5

Found: C, 51.67; H 4.07; N, 16.02%

C 15 H 1 2N40.2HC1.2/3 H 2 0 requires: C, 51.60; H, 3.85; N, 16.04%
Example 9

10 N-P-PyridylJ-N/.p-quinoIinyl) urea dihydrochloride

The title compound was prepared in 82% yield from 3-aminoquinoline and 3-pyridyl
isocyanate (D9) using a procedure similar to that in Example 8. m.p. 180-3°C.

15 NMR (d 6 -DMSO) 8: 7.60-7.97 (2H, m), 7.98-8.10 (1H, m), 8.10-8.28 (2H, m), 8.30-8.68
(2H, m), 8.75-8.96 (1H, m), 9.05-9.33 (2H, m), 10.70 (1H, s), 1 1.00 (1H, s).
Found: M + 264.1011 Ci5H 12 N 4 0 requires: 264.0991

Example 10

20 N-d-Methyl^-quinolinyO-N^S-pyridyl) urea dihydrochloride

The tide compound was prepared in 46% yield from 4-amino-2-methylquinoline and 3-
pyridyl isocyanate (D9) using a procedure similar to that described in example 8, except
that chloroform was substituted for dichloromethane and the whole was heated under reflux
25 for lh instead of being stirred at room temperature.

NMR (d 6 -DMSO) 8: 2.89 (3H, s), 7.78-7.79 (2H, m), 8.08 (1H, t, J=8 Hz), 8.16-8.26
(1H, m), 8.27-8.39 (1H, m), 8.50-8.84 (1H, m), 9.00-9.18 (1H, m), 11.26 (1H, s), 12.20
(1H, s).

30

Found: C54.62; H.4.54; N,15.82; CI 19.78%

Ci6Hi4N 4 0.2HC1.0.15H 2 0 requires: C54.31; H,4.64; N.15.83; CI 20.04%

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Example 11

N-(3-Pyridyl)-N'-(5-quinolinyl) urea dihydrochloride

5 The title compound was prepared in 67% yield from 5-aminoquinoline and 3-pyridyl
isocyanate (D9) using a procedure similar to that in Example 8. m.p. 251-2°.

NMR (d 6 -DMSO) 8: 7.85-8.10 (4H, m), 8.27-8.48 (2H, m) 8.49-8.65 (1H, m) 9.07-9.30
(2H, m), 9.39-9.58 (1H, m), 10.40 (1H, s), 11.30 (1H, s).

10

Found: C 54,17; H, 4.15; N, 16.48; CI 20.98%

C 15 H 12 N 4 0.2HC1 requires: C, 53.43; H, 4.18; N, 16.61; CI, 21.03%

Example 12

15 N-(3-Pyridyl)-N'-(8-quinolinyl) urea dihydrochloride

The title compound was prepared in 81% yield from 8-aminoquinoline and 3-pyridyl
isocyanate (D9) using a procedure similar to that in Example 8. m.p. 200-2°C.

20 NMR (d 6 -DMSO) 8: 7.50-7.83 (3H, m), 7.94-8.17 (1H, m), 8.30-8.75 (4H, m), 8.87-
9.08 (1H, m), 9.20-9.38 (1H, m), 10.02 (1H, s), 11.35 (1H, s).

Found: C, 53.37; H, 4.23; N 16.57; 20.80%

C 15 H 12 N 4 0.2HC1 requires: C, 53.43; H, 4.18; N, 16.61; CI, 21.03%

25

Example 13

N-(5-lndanyl)-N'(3-pyridyl) urea

The title compound was prepared in 56% yield from 5-aminoindane and nicotinoyl azide
30 using a procedure similar to that for Example 2, m.p. 197-199° C.

NMR (D 6 -DMSO) 5 : 2.00 (2H, m), 2.61 (4H, m), 7.15 (2H, m), 7.30 (1H, m), 7.39 (1H,
s), 7.94 (1H, d, J 8), 8.18 (1H, d, J 8), 861 (1H, s), 8.65 (1H, s), 8.78 (1H, s)

35 Found: C, 71.33; H, 6.17; N, 16.84%

C15H15N3O requires C, 71.13; H, 5.97; N, 16.59%
Found: M+ 253 C15N15N3O requires 253

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Example 14

N-(3-Pyridyl)-N'-(6-(l-methyl-l,2,3,4.tetrahydro)quinolinyl)urea

The title compound was prepared as in the method of Example 2 from 3-nicotinoyl azide
5 and 6-amino- 1 -methyl- 1 ,2,3,4-tetrahydroquinoline (D 1 3). Recrystallisation of the solid
obtained from methanol/ethyl acetate gave the title compound (0.85g, 66%) as a white
crystalline solid m.p. 174-6° C.

NMR (DMSO-d 6 ) 5: 1.82-1.93 (2H, m), 2.68 (2H, t, J 7), 2.79 (3H, s), 3.1 1 (2H, t, J 7),
10 6.51 (1H, d, J 10), 6.99-7.08 (2H, m), 7.23-7.31 (1H, m), 7.89-8.07 (1H, m), 8.12-8.17
(1H, m), 8.31 (1H, s), 8.55 (1H, s), 8.69 (1H, s)

Found: C, 67.69; H, 6.44; N, 19.71%
Cl6 H 18 N 4° requires C, 68.06; H, 6.43; N, 19.84%

15

Example 15

N-(l-methyl-5-indazolyI)-N'-(3-pyridyl)urea

The title compound was prepared in 93% yield from l-methyl-5-aminoindazole and
20 nicotinoyl azide using a procedure similar to that for Example 2, m.p. 200° C.

NMR (D 6 -DMSO) 5 : 4.01 (3H, s), 7.26-7.40 (2H, m), 7.57 (1H, d, J 8), 7.88-8.00 (3H,
m), 8.18 (1H, d, J 4), 8.61 (1H, d, J 3), 8.80 (1H, s), 8.85 (1H, s)

25 Found: C, 62.84; H, 4.89; N, 26.06%

Ci 4 H 13 N 5 0 requires C, 62.91; H, 4.90; N, 26.20%
Found: M + 267 Ci4H 13 N 5 0 requires 267

Example 16

30 N-(3-Methyl-5-benzo[b]thienyl)-N'-(3-pyridyl)urea

A solution of nicotinoyl azide (1.06g, 7.2mmol) in dry toluene (40ml) was heated under
reflux for 2h, then cooled. A solution of 5-arnino-3-methylbenzo[b]thiophene (N.B.
Chapman, K.Clarke and S.N. Sawhney, J.Chem.Soc (C), 1968, 518; 1.1 8g, 7.2 mmol) in
35 dry dichloromethane was added and the mixture was stirred overnight at room temperature.
The precipitate was filtered off, washed with petrol and recrystallised from

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dichloromethane/methanol/petrol, to give the title compound (1.64g, 80%),
mp. 202.5-203.5°C

Found: C, 63.18; H, 4.75; N, 14.78%
5 C 15 H 13 N 3 OS requires: C, 63.58; H, 4.62; N, 14.83%

NMR (d 6 -DMSO) 8: 2.32 (3H, s), 7.28-7.4 (3H, m), 7.85 (1H, d, J=8), 7.97 (1H, d, J=8),
7.99 (1H, s), 8.18 (1H, d, J=5), 8.61 (1H, d, J=2), 8.88 (1H, s), 8.95 (1H, s).

10 Example 17

N-(2-Methyl-5-benzo[b]thienyI)-N'-(3-pyridyl)urea

The title compound was prepared by a similar method to that described in Example 16,
starting from nicotinoyl azide (0.1 05g, 0.68 mmol) and 5-amino-2-methyl
1 5 benzo[b]thiophene (0. 1 1 g, 0.67mmol). The precipitate was filtered off, washed with petrol
and dried in vacuo to give the title compound (0.15g, 79%), mp 178-182°C.

Found: C, 63.24; H, 4.73; N, 14.97%

C15H13N3OS requires C, 63.58; H, 4.62; N, 14.83%

20

NMR (d 6 -DMSO) 8: 2.54 (3H, s), 7.08 (1H, s), 7.25-7.35 (2H, m), 7.74 (1H, d, J=8),
7.93-7.98 (2H, m), 8.19 (1H, d, J=5), 8.61 (1H, s), 8.88 (2H, s).

Example 18

25 N-(4-Methyl-5-benzo[b]thienyl)-N'-(3-pyridyl)urea

This compound was prepared by the method of Example 17, starting from nicotinoyl azide
(95mg, 0.65mmol) and 5-amino-4-methylbenzo[b]thiophene (0.1 05g, 0.64 mmol). Yield
0.15g, 83%, mp ~200°C (phase change), ~300°C (sublimation).

30

Found: C, 63.37; H, 4.66; N, 14.97%

C15H13N3OS requires C, 63.58; H, 4.62; N, 14.83%

NMR (d 6 -DMSO) 8: 3.37 (3H, s), 7.32 (1H, dd, J=8,5), 7.54 (1H, d, J=6), 7.65 (1H, d,
35 J=8), 7.76 (1H, d, J=6), 7.79 (1H, d, J=8), 7.98 (1H, dm, J=8), 8.18 (1H, d, J=5), 8.28
(1H, s), 8.62 (1H, d, J=2), 9.1 1 (1H, s)

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Example 19

N-(5-Benzo[b]thieny])-N'-(3-methyl-5-isoxazolyl)urea

To a solution of U'-carbonyldiimidazole (0.8 lg, 5mmol) in dry dichloromethane (25ml) at
5 0°C was added a solution of 5-amino-3-methylisoxazole (0.44g, 4.5 mmol) in dry
chloromethane (25ml). The mixture was stirred for lh at 0°C. Solvent was then
evaporated in vacuo and replaced by dry dimethylformamide (25ml). 5-Aminobenzo[b]
thiophene (0.67g, 4.5mmol) in dimethylformamide (5ml) was added and the mixture was
heated at 120°C for lh. After cooling, the mixture was poured into water and the
10 precipitate was filtered off, washed with water and dried. The crude product was extracted
with ethanol (in a Soxhlet apparatus) and the cooled ethanolic extract was filtered and
evaporated. The residue was chromatographed on silica gel eluted with 5%
methanol/dichloromethane and the first-eluted material was recrystallised from
dichloromethane/petrol to give the title compound (0.1 lg, 9%), mp >178°C (decomp.)

15

Found: C, 57.41; H, 4.21; N, 14.87%

Ci3H! iN 3 0 2 S requires C, 57.13; H, 4.06; N, 15.37%

NMR (d 6 - DMSO) 8: 2.17 (3H, s), 5.98 (1H, s), 7.37 (1H, dd, J=8,2), 7.43 (1H, d, J=5),
20 7.25 (1H, d, J=5), 7.92 (1H, d, J=8), 8.10 (1H, d, J=2), 8.95 (1H, s), 10.11 (1H, s)

Example 20

N-(5-Benzo[b]thienyl)-N'-(3-methyI-5-isothiazolyl)urea

25 This compound was prepared by a similar method to that described in Example 19, starting
from 5-amino-3-methylisothiazole hydrochloride (0.45g, 3mmol), carbonyldiimidazole
(0.53g, 3.3mmol) and 5-aminobenzo[b]thiophene (0.45g, 3mmol). Trielhylamine (0.42ml,
3mmol) was added to the solution of isothiazole hydrochloride before adding to the
carbonyldiimidazole solution. After addition to water, the crude product was washed with

30 water, dried, and recrystallised from dichloromethane/ethanol to give the title compound
(0.64g, 83%), mp. 221-224°C.

Found: C, 54.17; H, 4.00; N, 14.20%

CbH! iN 3 OS 2 requires: C, 53.96; H, 3.83; N, 14.52%

35

NMR (d 6 -DMSO) 8: 2.30 (3H, s), 6.68 (1H, s), 7.39 (1H, dd, J=8,2), 7.43 (1H, d, J=5),
7.76 (1H, d, J=5), 7.92 (1H, d, J=8), 8.12 (1H, d, J=2), 9.22 (1H, s), 10.38 (1H, s)

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WO 94/14801

PCT/EP93/03666

Pharmacological data

[3H]-mesulergine binding to rat 5-HTxc clones expressed in 293 cells in vitro

5 Evidence from the literature suggests that 5-HT2C antagonists may have a number

of therapeutic indications including the treatment of anxiety, migraine, depression, feeding
disorders and obsessive compulsion disorders. (Curzon and Kennett, 1990; Fozard and
Gray, 1989) and Alzheimer's Disease (Lawlor, 1989, J. Arch. Gen. Psychiat. Vol. 46
p.542).

10 The affinity of test drugs for the 5-HT2C binding site can be determined by

assessing their ability to displace [ 3 H]-mesulergine from 5-HT 2 c clones expressed in 293
cells (Julius et al., 1988). The method employed was similar to that of Pazos et al, 1984.

The cells suspension (50ml) was incubated with [ 3 H]-mesulergine (0.5nM) in Tris
HC1 buffer (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in the

15 presence of mianserin (10" 6 M). Ten concentrations of test drug (3 x 10' 9 to 10" 4 M final
concentration) were added in a volume of 50ml. The total assay volume was 500ml.
Incubation was stopped by rapid filtration using a Brandel cell harvester and radioactivity
measured by scintillation counting. The IC50 values were determined using a four
parameter logistic program PeLean 1978) and the piq (the negative logarithm of the

20 inhibition constant) calculated from the Cheng Prusoff equation where:

Ki = IC 50
1+C

25 _
Kd

Kj = inhibition constant.
C = concentration of [ 3 H]-mesulergine
30 Kd = Affinity of mesulergine for 5-HT2C binding sites.

Curzon, G.A. and Kennett, G.A. (1990). TIPS, Vol. 11, 181-182.
Fozard, J.R. and Gray, J.A. (1989). TIPS, Vol. 10, 307-309.
Pazos, A. et al. (1984). Eur. J. Pharmacol., 106, 531-538.
35 Julius et al. (1988) Science 241, 558-564

DeLean A, Munson P.J., Rodbaud D (1978) Am. J. Physiol 235, E97-E102.

Results: The compounds of examples 1 to 15 had a pKi of greater than 6.

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WO 94/14801

PCT/EP93/03666

Reversal of MCPP-induced Hypolocomotion

Administration of m-(chlorophenyl)piperazine (mCPP) to rats induces
hypolocomotion (Kennett and Curzon 1988, Luckie et al. 1989) as seen with the related
5 drug l-(m-trifluoromethylphenyl)piperazine (TFMPP) (Lucki and Frazer 1982, Kennett and
Curzon 1988). This effect was blocked by the non specific 5-HT2C/5-HT2 receptor
antagonists mianserin, cyproheptadine and metergoline and perhaps by mesulergine. It was
not blocked by the 5-HT2A receptor antagonists ketanserin and ritanserin at relevant doses
(Kennett and Curzon 1991) nor by antagonists of 5-HTja» 5-HTjb, 5-HT3, 0C2

10 adrenoceptors or dopamine D2 receptors. The effect of mCPP is therefore considered to
be mediated by 5-HT]c receptors (Kennett and Curzon 1988) as confirmed by subsequent
studies (Lucki et al, 1989). Since mCPP causes hypolocomotion when infused into the
cerebral ventricles this effect is probably centrally mediated (Kennett and Curzon 1988).
mCPP-induced hypolocomotion was measured in automated locomotion cages of

15 dimensions 56 cm long x WA cm wide x 25 cm high and made of black perspex. Two
photobeams traversed the width of the cages at either end at ground level. Sequential
breaking of these beams allowed the measurement of cage transits.

Male Sprague Dawley rats (200-250g) (Charles River) were housed in groups of
six. They were given drugs orally lh pretest and 40 mins later mCPP (7 mg/kg i.p.). After

20 a further 20 min they were placed in individual automated cages in groups of four under red
light in an adjacent room. After 10 min the test was terminated. Reversal of
mCPP-induced hypolocomotion was considered as evidence of in vivo central 5-HT2C
receptor antagonist properties.

25 Kennett, G.A., Curzon, G., (1988). Brit. J. Pharmacol. 94, 137-147.
Kennet G.A., Curzon, G., (1991). BritJ. Pharmacol. 103, 2016-2020.
Lucki, I., Frazer, A., (1982) Am. Soc. Neurosci. 8(abstr.), 101.
Lucki, I., Ward, M.R., Frazer, A., (1989). ^Pharmacol. Exp. Therap. 249, 155-164.

30 Result: The compound of Example 1 had an ID50 of 20.3 mg/kg p.o.

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WO 94/14801

PCT/EP93/03666

CLAIMS.

1 . A compound of formula (I) or a salt thereof:

<

2 3

wherein:

P is a quinoline, isoquinoline, or a 5- or 6-membered aromatic heterocyclic ring containing
10 up to three heteroatoms selected from nitrogen, oxygen or sulphur;

J is a ring system selected from quinoline, tetrahydroquinoline, indoline, indazole,

benzothiophene, indene, indane, benzothiazole or benzofuran;

R 1 is hydrogen, Ci_6 alkyl, halogen, NR 5 R 6 or OR 7 , where R 5 , R 6 and R 7 are

independently hydrogen or Cj_6 alkyl; and
15 R 2 and R 3 are independently hydrogen or Cj.g alkyl.

R 4 is Ci_6 alkyl, OR 8 or halogen, where R 8 is hydrogen or C\.(, alkyl; and

n is 1 or 2;

provided that:

• when P is other than pyridyl, J is not indoline,

20 • P and J are not both 6-methoxy quinoline, 8-hydroxy quinoline or 2-methyl quinoline,

• when J is quinoline or 2-methyl quinoline, P is not 2-thiazolyl,

• when P and J are both quinoline and r!,R 2 and R 3 are all hydrogen, R 4 is not
hydrogen or 6-methoxy.

25 2. A compound according to claim 1 in which P is 3-pyridyl.

3. A compound according to claim 1 or 2 in which R 1 , R 2 , and R 3 are all hydrogen.

4. A compound according to claim 1 which is
30 N-5-(Benzo[b]thienyl)-N'-(3-pyridyl)urea

N-(5-Indenyl)-N'-(3-pyridyl)urea
N-( 1 , 1 -Dimethyl-5-indenyl)-N'-(3-pyridyl) urea
N-(5-Benzothiazolyl)-N'-(3-pyridyl) urea
N-(5-Benzofuryl)-N'-(3-pyridyl) urea
35 N-(l-Methyl-5-indolinyl)-N'-(3-pyridyl)urea

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WO 94/14801

PCT/EP93/03666

N-(3-Pyridyl)-N'-(3-quinolinyl) urea
N-(3-Pyridyl)-N-(6-quinolinyl) urea
N-(2-Methyl-4-quinolinyl)-N-(3-pyridyl) urea
N-5-(Benzo[b]thienyl)-N-(2-methyl-4-quinolyl)urea
5 N-(3-Pyridyl)-N'-(5-quinolinyl) urea
N-(3-Pyridyl)-N-(8-quinolinyl) urea
N-(5-Indanyl)-N(3-pyridyl) urea

N-(3-Pyridyl)-N'-(6-( 1 -methyl- 1 ,2,3 ,4-tetrahydro)quinolinyl)urea
N-( 1 -methyl-5-indazolyl)-N'-(3-pyridyl)urea

10 N-(3-Methyl-5-benzo[b]thienyl)-N'-(3-pyridyl)urea
N-(2-Methyl-5-benzo[b]thienyl)-N'-(3-pyridyl)urea
N-(4-Methyl-5-benzo[b]thienyl)-N'-(3-pyridyl)urea
N-(5-Benzo[b]thienyl)-N'-(3-methyl-5-isoxazolyl)urea
N-(5-Benzo[b]thienyl)-N'-(3-methyl-5-isothiazolyl)urea

1 5 and pharmaceurically acceptable salts thereof.

5. A process for the preparation of a compound of formula (I) or a pharmaceurically
acceptable salt thereof, which comprises:

20 the coupling of a compound of formula (II);

with a compound of formula (HI);

wherein P is as defined in relation to formula (I), A and B contain the appropriate functional
group(s) necessary to form the moiety, -NR 2 CONR 3 ' when coupled, the variables R 1 ',
30 R 2 ', R 3 ' and J' are R 1 , R 2 R 3 , and J respectively, as defined in formula (I), or groups

convertible thereto, and thereafter optionally and as necessary and in any appropriate order,
converting any R 1 ', R 2 ', R 3 ' and J', when other than R 1 , R 2 , R 3 and J respectively to R 1 ,
R 2 , r 3 and J, interconverting R 1 , R 2 R 3 and J and forming a pharmaceurically acceptable
salt thereof.

35

6. A compound of formula (III) as defined in claim 5.

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WO 94/14801

PCT/EP93/03666

7. A compound according to any one of claims 1 to 4 for use in therapy.

8. A pharmaceutical composition which comprises a compound according to any one
5 of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.

9. Use of a compound of formula (IA) or a pharmaceutically acceptable salt thereof:

2 3

R R

l I

10

(IA)

wherein:

P is a quinoline, isoquinoline, or a 5- or 6-membered aromatic heterocyclic ring containing
15 up to three heteroatoms selected from nitrogen, oxygen or sulphur;

J is a ring system selected from quinoline, tetrahydroquinoline, indoline, indazole,

benzothiophene, indene, indane, benzothiazole or benzofuran;

r1 is hydrogen, Ci_6 alkyl, halogen, NR 5 R 6 or OR 7 , where R 5 , R 6 and R 7 are

independently hydrogen or Ci_6 alkyl; and
20 R 2 and R 3 are independendy hydrogen or C \ _6 alkyl.

r4 i s Ci_6 alkyl, OR 8 or halogen, where R 8 is hydrogen or Ci_6 alkyl; and

n is 1 or 2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament

for the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive

compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks,
25 withdrawal from drug abuse, schizophrenia and/or also disorders associated with spinal

trauma and/or head injuries

1 0. A method of treatment or prophylaxis of anxiety, depression, migraine, anorexia,
obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks,

30 withdrawal from drug abuse, schizophrenia and/or disorders associated with spinal trauma
and/or head injuries, in mammals including humans, which comprises administering to the
sufferer a therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.

-26-

INTERNATIONAL SEARCH REPORT

Intern al Application No

PCT/EP 93/03666

A. CLASSIFICATION OF SUBJECT MATTER . ^ .„ „„„ . .~ „

IPC 5 C07D409/12 A61K31/33 C07D213/75 C07D417/12
C07D403/12 C07D413/12

According to International Patent Classification (IPC) or to both national classification and IPC

C07D401/12

B. FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols)

IPC 5 C07D A61K

Documentation searched other than minimum documentation to the extent mat such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practical, search terms used)

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category * Citation of document, with indication, where appropriate, of the relevant passages

Relevant to claim No.

P.X

P,X

W0,A,92 05170 (BEECHAM GROUP PLC) 2 April
1992

* complete document *

WO, A, 93 16694 (SMITH-KLINE BEECHAM PLC) 2
September 1993

* complete document *

WO, A, 93 18028 (SMITH-KLINE BEECHAM PLC) 16
September 1993

* complete document *

1,6,8,9
1,6,8,9
1,6,8,9

□

Further documents are listed in the continuation of box C.

Patent family members are listed in annex.

' Special categories of cited documents :

'A' document defining the general state of the art which is not

considered to be of particular relevance
'E* earlier document but published on or after the international

filing date

"L* document which may throw doubts on priority claimfs) or
which is cited to establish the publication date of another
citation or other special reason (as specified)

'O* document referring to an oral disclosure, use, exhibition or
other means

*P* document published prior to the international filing date but
later than the priority date claimed

"T" later document published after the international filing date
or priority date and not in conflict with the application but
cited to understand the principle or theory underlying the
invention

"X* document of particular relevance; the claimed invention
cannot be considered novel or cannot be considered to
involve an inventive step when the document is taken alone

"Y* document of particular relevance; the claimed invention
cannot be considered to involve an inventive step when the
document is combined with one or more other such docu-
ments, such combination being obvious to a person skilled
in the art.

'&' document member of me same patent family

Date of the actual completion of the international search

23 March 1994

Date of mailing of the international search report

- 5. Oi 9H

Name and mailing address of the ISA

European Patent Office, P.B. 5818 Patentlaan 2
NL - 2280 HV Rijswijk
Tel. (+31-70) 340.2040, Tx. 31 651 epo nl,
Fax: (+31-70)340-3016

Authorized officer

Van Bijlen, H

Form PCT/ISA/210 (ucond thaat) (July 1993)

INTERNATIONAL SEARCH REPORT

I national application No.

PCT/EP 93/ 03666

Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)

This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:

1. | | Claims Nos.:

because they relate to subject matter not required to be searched by this Authority, namely:

Although claim 10 1s directed to a method of treatment of (diagnostic
method practised on) the human/animal body, the search has been carried
out and based on the alleged effects of the compound/composition.

2. Claims Nos.:

because they relate to parts of the international application that do not comply with the prescribed requirements to such
an extent that no meaningful international search can be carried out, specifically:

3. | | Claims Nos.:

because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).

Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet)

This International Searching Authority found multiple inventions in this international application, as follows:

1 . As all required additional search fees were timely paid by the applicant, this international search report covers all
searchable claims.

2. | | As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment

of any additional fee.

3. As only some of the required additional search fees were timely paid by the applicant, this international search report

covers only those claims for which fees were paid, specifically claims Nos.:

4. [ [ No required additional search fees were timely paid by the applicant. Consequently, this international search report is
restricted to the invention first mentioned in the claims; it is covered by claims Nos.:

Remark on Protest | | The additional search fees were accompanied by the applicant's protest.

| | No protest accompanied the payment of additional search fees.

Form PCT/ISA/210 (continuation of first sheet (1)) (July 1992)

INTERNATIONAL SEARCH REPORT

.ormaaon on patent family members

Inten al Application No

PCT/EP 93/03666

Patent document

Publication

Patent family

Publication

cited in search report

date

member(s)

date

WO-A-9205170

02-04-92

AU-B-

642041

07-10-93

AU-A-

8503891

10 UH 3L.

CA-A-

2091246

14-03-92

EP-A-

0550507

If U/

JP-T-

6500551

20-01-94

WO-A-9316694

02-09-93

AU-B-

3638393

13-09-93

WO-A-9318028

16-09-93

N0NE

Form FCT/ISA/310 (patent family annex) (July 1993)